Peripheral T-cell lymphoma (PTCL) is an uncommon lymphoma that is often challenging to diagnose and classify. Most patients also have poor survival with standard mulfiagent chemotherapy and new, more effecfive therapeufic approaches are necessary to improve patient outcome. Our experience in using gene expression proflling (GEP) to study B-cell lymphomas indicates that this approach is very promising in improving classificafion, construcfing molecular based prognosticators and detecfing biologically significant pathways that may be targeted for treatment. We hypothesized that GEP will allow us to construct robust and biologically meaningful classifiers for PTCL and will also allow us to idenfify therapeutically relevant oncogenic pathways and tumor/host interactions that would lead to improvement in the management of pafients with PTCL. Our aims are: 1) Identify key molecular signatures in PTCL and natural killer (NK) cell malignancies to construct a more robust and biologically meaningful classificafion. 2) Identify oncogenic pathways and tumor/host interacfions that contribute to the development of the neoplastic clone, tumor- induced immunosuppression and the outcome of patients with PTCL with particular emphasis on angioimmunoblasfic T-cell lymphoma (AITL). 3) To perform a phase l/ll trial in pafients with relapsed PTCL with agents that are directed at targets idenfified by GEP. Since PTCL is an uncommon disease, this study will draw on the fissue and clinical resources of several large completed and on-going projects for both discovery and validation. The participafion of two large medical centers (UNMC and M.D. Anderson) with strong emphasis on lymphoma management will provide the pafient population for the initial clinical trial. Additional efforts in the recruitment of subjects and involvement of other SPORES funded institufions are anficipated for the second trial based on the basic and clinical studies in the first two years of the project. We believe that this study will lead to novel targeted therapies that will significantly improve the outcome of patients with PTCL while reducing treatment related toxicity. RELEVANCE (See instructions): Most patients with PTCL have poor outcome with current chemotherapeufic regimens. Our proposal will lead to a better characterization of the disease including the oncogenic pathways that are often activated and the role of the microenvironmenL It will lead to novel therapeutic approaches that will improve survival of these pafients.